Use of zinc derivatives as cyclic ester polymerization catalysts

ABSTRACT

The invention concerns the use of zinc derivatives of general formula (I) wherein: L 1  represents a group of formula: —E 14 (R 14 )(R′ 14 )(R″ 14 ), —E 15 (R 15 ) (R′ 15 ) or —E 16 (R 16 ); E is an atom of group 15; L 2  and L 3  independently represent a group of formula: —E 14 (R 14 )(R′ 14 )(R″ 14 ), —E 15 (R 15 )(R′ 15 ) or —E 16 (R 16 ), or together form a chain of formula —L′ 2 —A—L′ 3 —; A represents a saturated or unsaturated chain comprising one, two or three elements of group 14; L′ 2  and L′ 3  independently represent a group of formula —E 14 (R 14 )(R′ 14 ) —E 15 (R 15 ) or —E 16 —; E 14  is an element of group 14; E 15  is an element of group 15; E 16  is an element of group 16; R 14 , R′ 14 , R″ 14 , R 15 , R′ 15  and R 16  represent various groups, as (co) polymerisation catalysts of cyclic esters

This application is a 371 of PCT/FR02/01220 filed Apr. 9, 2002.

Over the last twenty years, biodegradable polymers have undergoneconsiderable development. In particular, polyesters such aspoly-ε-caprolactones, polylactides and polyglycolides are well adaptedfor a number of industrial (packaging, products for domestic use etc.),pharmaceutical (controlled- and sustained-release systems) and medical(suture elements, prostheses etc.) applications. They are generallyprepared by polymerization by ring opening using metal derivatives, inparticular of aluminium, tin and zinc (Kuran Prog. Polym. Sci. 1998, 23,919). These polymerizations are most often carried out in aheterogeneous medium and lead to fairly wide mass distributions.

Of all the polyesters, the copolymers appear as “tailor-made”macromolecules. Depending on the uses sought, their properties can infact be adjusted by acting on different parameters (chain length andmass distribution but also the nature, proportion and chain formation ofthe monomers and also the nature of the chain ends). There is thereforea need for new homogeneous phase polymerization processes making itpossible to control all of these parameters.

In this field, during the last few years, work has been directed chieflytowards new more or less sophisticated catalytic systems such asporphyrin ligand systems [Inoue Acc Chem Res (1996) 29, 39],diamido-amine [Bertrand J Am Chem Soc (1996) 118, 5822; Organometallics(1998) 17, 3599] or also β-diiminate [Coates J Am Chem Soc (1999) 121,11583; Polym. Prep. (1999) 40, 542].

The present invention proposes a cyclic ester (co)polymerization processwhich is both simple and effective, having a number of advantages, inparticular:

-   -   the zinc-based (co)polymerization catalysts used are easily        accessible and inexpensive; they are not toxic or only slightly        toxic. These are well defined compounds (they exist in monomer        and/or dimer form);    -   the (co)polymerization can in fact be carried out in a        homogeneous medium in order that the mass distribution of the        (co)polymers obtained is restricted; such a process is highly        suitable for the preparation of block copolymers. The successive        addition of monomers makes it possible in particular to obtain        block copolymers. Finally the process makes it possible to        completely control the nature of the ends of the (co)polymers.

A subject of the present invention is therefore the use of zincderivatives of general formula (1)

in which

-   -   L₁ represents a group of formula —E₁₄(R₁₄)(R′₁₄)(R″₁₄),        —E₁₅(R₁₅)(R′or —E₁₆(R₁₆);    -   E is an atom of group 15;    -   L₂ and L₃ represent, independently, a group of formula        —E₁₄(R₁₄)(R′₁₄)(R″₁₄), —E₁₅(R₁₅)(R′₁₅) or —E₁₆(R₁₆), or form        together a chain of formula —L′₂—A—L′₃—;    -   A represents a saturated or unsaturated chain comprising one,        two or three elements of group 14, each being optionally and        independently substituted by one of the following substituted        (by one or more identical or different substituents) or        non-substituted radicals: alkyl, cycloalkyl, aryl, in which said        substituent is a halogen atom, the alkyl, aryl, nitro or cyano        radical;    -   L′₂ and L′₃ represent, independently, a group of formula        —E₁₄(R₁₄)(R′₁₄)—, —E₁₅(R₁₅)— or —E₁₆—;    -   E₁₄ is an element of group 14;    -   E₁₅ is an element of group 15;    -   E₁₆ is an element of group 16;    -   R₁₄, R′₁₄, R″₁₄, R₁₅, R′₁₅ and R₁₆ represent, independently, the        hydrogen atom; one of the following substituted (by one or more        identical or different substituents) or non-substituted        radicals: alkyl, cycloalkyl or aryl, in which said substituent        is a halogen atom, the alkyl, cycloalkyl, aryl, nitro or cyano        radical; a radical of formula —E′₁₄RR′R″;    -   E′₁₄ is an element of group 14;    -   R, R′ and R″ represent, independently, the hydrogen atom or one        of the following substituted (by one or more identical or        different substituents) or non-substituted radicals: alkyl,        cycloalkyl, aryl, in which said substituent is a halogen atom,        the alkyl, aryl, nitro or cyano radical;        as cyclic ester (co)polymerization catalysts.

In the definitions indicated above, the expression halogen represents afluorine, chlorine, bromine or iodine, preferably chlorine atom. Theexpression alkyl preferably represents a linear or branched alkylradical having 1 to 6 carbon atoms and in particular an alkyl radicalhaving 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl radicals.

The cycloalkyl radicals are chosen from the saturated or unsaturatedmonocyclic cycloalkyls. The saturated monocyclic cycloalkyl radicals canbe chosen from the radicals having 3 to 7 carbon atoms such as thecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptylradicals. The unsaturated cycloalkyl radicals can be chosen from thecyclobutene, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadieneradicals.

The aryl radicals can be of mono- or polycyclic type. The monocyclicaryl radicals can be chosen from the phenyl radicals optionallysubstituted by one or more alkyl radicals such as tolyl, xylyl, mesityl,cumenyl. The polycyclic aryl radicals can be chosen from the naphthyl,anthryl, phenanthryl radicals.

The compounds of formula (1) can be presented in cyclic monomer and/ordimer form:

The compounds of formula (1) can comprise one or more solvent molecules[zinc complexes with one or two tetrahydrofuran molecules have beenisolated and fully characterized: K. G. Caulton et al., Inorg. Chem.(1986) 25, 1803; D. J. Darensbourg et al., J. Am. Chem. Soc. (1999) 121,107] or alternatively one or more phosphines [zinc complexes with one ortwo phosphine molecules have been isolated and fully characterized: D.J. Darensbourg et al., Inorg. Chem. (1998) 37, 2852 and ibid. (2000) 39,1578]. The expression solvent represents an aromatic hydrocarbon such asbenzene, toluene; a cyclic or acyclic dialkyl ether such asdiethylether, dioxane, tetrahydrofuran, ethyltertiobutylether; achlorinated solvent such as dichloromethane, chloroform; an aliphatic oraromatic nitrile such as acetonitrile, benzonitrile; an aliphatic oraromatic, cyclic or acyclic ketone such as acetone, acetophenone,cyclohexanone; an aliphatic or aromatic, cyclic or acyclic carboxylicacid derivative such as ethyl acetate, dimethylformamide. The expressionphosphine represents an aromatic and/or aliphatic tertiary phosphinesuch as triphenylphosphine, diphenylmethylphosphine,dimethylphenylphosphine, tributylphosphine, trimethylphosphine.

A more particular subject of the invention is the use, as cyclic ester(co)polymerization catalysts, of the compounds of general formula (1) asdefined above, characterized in that

-   -   E is a nitrogen or phosphorus atom;    -   E₁₄ is a carbon or silicon atom;    -   E₁₅ is a nitrogen or phosphorus atom;    -   E₁₆ is an oxygen or sulphur atom;    -   A represents a saturated or unsaturated chain comprising one,        two or three elements of group 14, each being optionally and        independently substituted by an alkyl or aryl radical;    -   R₁₄, R′₁₄, R″₁₄, R₁₅, R′₁₅ and R₁₆ represent, independently, the        hydrogen atom, an alkyl radical, an aryl radical or a radical of        formula —E′₁₄RR′R″;    -   E′₁₄ is a carbon or silicon atom;    -   R, R′ and R″ represent, independently, the hydrogen atom or an        alkyl radical,        and preferably,    -   E is a nitrogen atom;    -   E₁₄ is a carbon atom;    -   E₁₅ is a nitrogen atom;    -   E₁₆ is an oxygen or sulphur atom;    -   R₁₄, R′₁₄, R″₁₄, R₁₅ and R′₁₅ represent independently an alkyl        radical or radical of formula —E′₁₄RR′R″;    -   R₁₆ represents an alkyl or aryl radical optionally substituted        by one or more substituents chosen from the alkyl radicals and        halogen;    -   E′₁₄ represents a silicon atom;    -   R, R′ and R″ represent, independently, the hydrogen atom or a        methyl, ethyl, propyl or isopropyl radical.

A more particular subject of the invention is also the use, as cyclicester (co)polymerization catalysts, of the compounds of general formula(1) as defined above, characterized in that

-   -   L₁ represents a group of formula —E₁₅(R₁₅)(R′₁₅);    -   L₂ and L₃ represent, independently, a group of formula        —E₁₄(R₁₄)(R′₁₄)(R″₁₄); and preferably    -   E is a nitrogen atom;    -   E₁₅ is a nitrogen atom;    -   R₁₄, R′₁₄, R″₁₄, R₁₅ and R′₁₅ represent independently an alkyl        radical or radical of formula —E′₁₄RR′R″;    -   R, R′ and R″ represent, independently, an optionally substituted        alkyl radical.

Very preferentially, the compound of formula (1) as defined above,corresponds to the following formula: [(Me₃Si)₂N]₂Zn.

Certain of the compounds of formula (1) are known products, i.e. thesynthesis and the characterization of which have been described [H.Burger, W. Sawodny, U. Wannagat, J. Organometal. Chem. (1965) 3, 113; K.Hedberg et al., Inorg Chem. (1984) 23, 1972; P. P. Power et al., Inorg.Chem. (1991) 30, 5013; H. Schumann et al., Z. Anorg. Allg. Chem. (1997)623, 1881 and ibid. (2000) 626, 747]. As a result, the new compounds offormula (1) can be prepared by analogy with the synthesis routes alreadydescribed.

The invention relates to the use of the products of formula (1) asdefined above, as catalysts for the implementation of cyclic ester(co)polymerization, i.e. polymerization or copolymerization of cyclicesters. During the implementation of these (co)polymerizations, thecompounds according to the invention play the role of chain initiatorand/or regulator.

The cyclic esters can range in size from four to eight members. As anexample of cyclic esters corresponding to the above formulation,ε-caprolactone and the cyclic ester polymers of lactic and/or glycolicacid can be mentioned. Random or block copolymers can be obtained,depending on whether the monomers are introduced together at the startof the reaction, or sequentially during the reaction.

A subject of the invention is also a process for preparing random orblock polymers or copolymers, which consists of bringing together one ormore monomers, a chain initiator, a polymerization catalyst, andoptionally an additive, said process characterized in that the chaininitiator and the polymerization catalyst are represented by the samecompound which is chosen from the compounds of formula (1) as definedabove.

The expression additive represents any protic reagent such as water,hydrogen sulphide, ammonia, an aliphatic or aromatic alcohol, analiphatic or aromatic thiol, a primary or secondary, aliphatic oraromatic, cyclic or acyclic amine. This reagent is capable of exchangingone of the substituents of the product of formula (1), which makes itpossible to control the nature of one of the chain ends.

The (co)polymerization can be carried out either in solution or insuperfusion. When the (co)polymerization is carried out in solution, thereaction solvent can be the (or one of the) substrate(s) used in thecatalytic reaction. Solvents which do not interfere with the catalyticreaction itself, are also suitable. As examples of such solvents,saturated or aromatic hydrocarbons, ethers, the aliphatic or aromatichalides can be mentioned.

The reactions are carried out at temperatures comprised between ambienttemperature and approximately 250° C.; the temperature range comprisedbetween 20 and 180° C. has proved most advantageous. The reaction timesare comprised between a few minutes and 300 hours, and preferablybetween 5 minutes and 72 hours.

This (co)polymerization process is particularly suitable for obtainingcyclic ester (co)polymers, in particular the cyclic ester polymers oflactic and/or glycolic acid. The products obtained such as glycoliclactic copolymers are biodegradable, and are advantageously used as asupport in sustained release therapeutic compositions.

The invention finally relates to polymers or copolymers which can beobtained by the implementation of a process as described above.

Unless otherwise specified, all the technical and scientific terms usedin the present Application, have the same meaning as that usuallyunderstood by an ordinary specialist in the field to which the inventionbelongs. Similarly, all the publications, patent applications and allother references mentioned in the present Application, are incorporatedby way of reference.

The following examples are presented in order to illustrate the aboveprocedures and should in no event be considered as a limit to the scopeof the invention.

EXAMPLE 1

Preparation of an Oligomer with Controlled Chain Ends (amido-alcohol)H₂N-(D,L-lactide)_(n)-H

0.2 g (0.52 mmol) of [(Me₃Si)₂N]₂Zn and 10 ml of dichloromethane areintroduced successively into a Schlenk tube equipped with a magneticstirrer and purged under argon. 0.6 g (4.16 mmol) of D,L-lactide insolution in 30 ml of dichloromethane is added to the preceding solution.The reaction mixture is left under stirring at 40° C. for 20 hours.Proton NMR analysis of an aliquot shows that the conversion of theD,L-lactide is greater than 95%. 0.5 ml of methanol is added to thepreceding solution and stirring is maintained for 10 minutes.Evaporation of the solvent followed by extraction with acetonitrilemakes it possible to isolate the oligomer in the form of a white solid.The nature of the chain ends of this oligomer is determined by massspectrometry (electrospray ionization, positive ion mode detection,sample dissolved in acetonitrile with a trace of ammonium hydroxide).

EXAMPLE 2

Preparation of an Oligomer with Controlled Chain Ends (ester-alcohol)i-PrO-(D,L-lactide)_(n)-H

0.2 g (0.52 mmol) of [(Me₃Si)₂N]₂Zn, 40 μl (0.52 mmol) of isopropanoland 10 ml of dichloromethane are introduced successively into a Schlenktube equipped with a magnetic stirrer and purged under argon.. Thereaction mixture is left under stirring at ambient temperature for 10minutes. After the addition of 0.6 g (4.16 mmol) of D,L-lactide insolution in 20 ml of dichloromethane, the reaction medium is left understirring at ambient temperature for 60 hours. Proton NMR analysis of analiquot shows that the conversion of the D,L-lactide is greater than95%. 0.5 ml of methanol is added to the preceding solution and stirringis maintained for 10 minutes. Evaporation of the solvent followed byextraction with acetonitrile makes it possible to isolate the oligomerin the form of a white paste. The nature of the chain ends of thisoligomer is determined by proton NMR and by mass spectrometry(electrospray ionization, positive ion mode detection, sample dissolvedin acetonitrile with a trace of ammonium hydroxide).

EXAMPLE 3

Preparation of an Oligomer with Controlled Chain Ends (ester-anhydride)i-PrO-(D,L-lactide)_(n)-COCH₃

0.2 g (0.52 mmol) of [(Me₃Si)₂N]₂Zn, 40 μl (0.52 mmol) of isopropanoland 10 ml of dichloromethane are introduced successively into a Schlenktube equipped with a magnetic stirrer and purged under argon. Thereaction mixture is left under stirring at ambient temperature for 10minutes. After the addition of 0.6 g (4.16 mmol) of D,L-lactide insolution in 20 ml of dichloromethane, the reaction medium is left understirring at ambient temperature for 24 hours. Proton NMR analysis of analiquot shows that the conversion of the D,L-lactide is greater than95%. 0.2 ml of acetic anhydride is added to the preceding solution andthe stirring is maintained for 10 minutes. Evaporation of the solventfollowed by extraction with acetonitrile makes it possible to isolatethe oligomer in the form of a white paste. The nature of the chain endsof this oligomer is determined by proton NMR and by mass spectrometry(electrospray ionization, positive ion mode detection, sample dissolvedin acetonitrile with a trace of ammonium hydroxide).

EXAMPLE 4

Preparation of a Random Copolymer (D,L-lactide/glycolide) of Mass 15,000having a lactide/glycolide Composition close to 50/50

3.92 g (27.3 mmol) of D,L-lactide, 3.11 g (27.3 mmol) of glycolide, and12 ml of mesitylene are introduced successively into a Schlenk tubeequipped with a magnetic stirrer and purged under argon then, a solutionof 0.07 g (0.18 mmol) of [(Me₃Si)₂N]₂Zn in 1 ml of mesitylene isintroduced at 180° C. The reaction mixture is left under stirring at180° C. for 2 hours. Proton NMR analysis makes it possible to verifythat the conversion is 94% for the lactide and 100% for the glycolide.The ratio of the signal integrals corresponding to the polylactide part(5.20 ppm) and polyglycolide part (4.85 ppm) makes it possible toevaluate the composition of the copolymer at 50% lactide and 50%glycolide. According to GPC analysis, using a calibration carried outfrom PS standards of masses 761 to 400,000, this copolymer is a mixtureof macromolecules (Mw/Mn=1.98) of fairly low masses (Mw=15,000 Dalton).

EXAMPLE 5

Preparation of a Random Copolymer (D,L-lactide/glycolide) of Mass 35,000having a lactide/glycolide Composition close to 50/50

7.84 g (54.6 mmol) of D,L-lactide, 6.22 g (54.6 mmol) of glycolide and12 ml of mesitylene are successively into a Schlenk tube equipped with amagnetic stirrer and purged under argon then, a solution of 0.07 g (0.18mmol) of [(Me₃Si)₂N]₂Zn in 1 ml of mesitylene is introduced at 180° C.The reaction mixture is left under stirring at 180° C. for 2 hours.Proton NMR analysis makes it possible to verify that the conversion is78% for the lactide and 100% for the glycolide. The ratio of the signalintegrals corresponding to the polylactide part (5.20 ppm) andpolyglycolide part (4.85 ppm) makes it possible to evaluate thecomposition of the copolymer at 47% lactide and 53% glycolide. Accordingto GPC analysis, using a calibration carried out from PS standards ofmasses 761 to 400,000, this copolymer is a mixture of macromolecules(Mw/Mn=1.56) of fairly high masses (Mw=35,000 Dalton).

EXAMPLE 6

Preparation of a Random Copolymer (D,L-lactide/glycolide) of Masse45,000 having a lactide/glycolide Composition close to 50/50

3.92 g (27.2 mmol) of D,L-lactide, 3.11 g (27.2 mmol) of glycolide and13 ml of mesitylene are introduced successively into a Schlenk tubeequipped with a magnetic stirrer and purged under argon. Then, asolution of 70 mg (0.18 mmol) of [(Me₃Si)₂N]₂Zn and 14 μl (0.18 mmol) ofisopropanol in 2 ml of mesitylene is added at 180° C. The reactionmixture is left under stirring at 180° C. for 2 hours. Proton NMRanalysis makes it possible to verify that the conversion is 80% for thelactide and 100% for the glycolide. The ratio of the signal integralscorresponding to the polylactide part (5.20 ppm) and polyglycolide part(4.85 ppm) makes it possible to evaluate the composition of thecopolymer at 44% lactide and 56% glycolide. According to GPC analysis,using a calibration carried out from PS standards of masses 761 to400,000, this copolymer is a mixture of macromolecules (Mw/Mn=1.65) offairly high masses (Mw=45,000 Dalton).

EXAMPLE 7

Preparation of a Block Copolymer (D,L-lactide/glycolide)

4.7 g (33.5 mmol) of D,L-lactide, and 15 ml of mesitylene are introducedsuccessively into a Schlenk tube equipped with a magnetic stirrer andpurged under argon. Then, a solution of 86 mg (0.22 mmol) of[(Me₃Si)₂N]₂Zn and 17 μl (0.22 mmol) of isopropanol in 3 ml ofmesitylene is added at 180° C. The reaction mixture is left understirring at 180° C. for 2 hours. Proton NMR analysis makes it possibleto verify that the conversion of the monomer is total. 0.5 g (4.5 mmol)of glycolide is added to the preceding solution, maintained understirring at 180° C. The reaction mixture is left under stirring at 180°C. for 1 hour. Proton NMR analysis of an aliquot shows that theconversion of the lactide and of the glycolide is total and that acopolymer is formed. The ratio of the signal integrals corresponding tothe polylactide part (5.20 ppm) and polyglycolide part (4.85 ppm) is9/1. GPC analysis indicates that this copolymer is a mixture ofmacromolecules of low polydispersity index (Mw=20 400 Dalton,Mw/Mn=1.41).

1. In the (co)polymerization of cyclic esters, the improvementcomprising using as catalyst zinc derivatives of the formula

wherein L₁ is selected from the group consisting of—E₁₄(R₁₄)(R′₁₄)(R″₁₄), —E₁₅(R₁₅)(R′₁₅) and —E₁₆(R₁₆); E is nitrogen orphosphorous; L₂ and L₃ are, independently, selected from the groupconsisting of —E₁₄(R₁₄)(R′₁₄)(R″₁₄), —E₁₅(R₁₅)(R′₁₅) and —E₁₆(R₁₆), E₁₄is carbon or silicon; E₁₅ is nitrogen or phosphorous; E₁₆ is oxygen orsulfur; R₁₄, R′₁₄, R″₁₄, R₁₅, R′₁₅ and R₁₆ are, independently selectedfrom the group consisting of hydrogen, alkyl, aryl and E′_(—14)RR′R″;E′₁₄ is carbon or silicon; R, R′ and R″ are, independently, hydrogen oralkyl.
 2. The polymerization process of claim 1 wherein E is nitrogen;E₁₄ is carbon; E₁₅ is nitrogen; E₁₆ is oxygen or sulfur; R₁₄, R′₁₄,R″₁₄, R₁₅ and R′₁₅ are independently alkyl or —E′_(—14)RR′R″; R₁₆ isalkyl or aryl optionally substituted by at least one alkyl and halogen;E′₁₄ is silicon; R, R′ and R″ are, independently selected from the groupconsisting of hydrogen methyl, ethyl, propyl and isopropyl.
 3. Thepolymerization process of claim 1 wherein L₁ is —E₁₅(R₁₅)(R′₁₅); L₂ andL₃ are, independently, —E₁₄(R₁₄)(R′₁₄)(R″₁₄).
 4. The polymerizationprocess of claim 1 wherein E is a nitrogen atom; E₁₅ is a nitrogen; R₁₄,R′₁₄, R″₁₄, R₁₅ and R′₁₅ are, independently, alkyl or —E′_(—14)RR′R″;R,R′ and R″ are, independently, optionally substituted alkyl.
 5. In thepolymerization of cyclic esters, the improvement of comprising using asthe catalyst, [(Me₃Si)₂N]₂Zn.
 6. The polymerization process of claim 1wherein cyclic ester polymers are lactic and/or glycolic acid polymers.7. In a process for the preparing block or random copolymers, orpolymers, which consists of bringing together one or more monomers, apolymerization catalyst and, optionally, an additive, optionally apolymerization solvent, at a temperature between ambient temperature and250° C. for a period of a few minutes and 300 hours, the improvementcomprising using as the chain initiator and the polymerization catalysta compound of (I) as defined in claim
 1. 8. The process of claim 7wherein the monomer is a cyclic ester polymer of lactic and/or glycolicacid.